Severe malaria kills about 900,000 children a year and may impair brain function in some survivors. Severe malaria pathogenesis causes dysfunction in multiple organs and systems in the infected host. We have reported [PLoS One, 2012;7(3):e34280)] that excess production of heme, a by-product of Plasmodium (P. berghei)-damaged erythrocytes, produced during infection is central to the pathogenesis of fatal experimental cerebral malaria (ECM). We reported for the first time that excess free heme induces up-regulation of STAT3 and CXCL10 and confirmed that up-regulation of HO-1 prevents inflammation and tissue damage in brain as well as other organs during ECM. Following a screen for agents that attenuate ECM, we identified Neuregulin- 1, a 8 kDa peptide currently undergoing clinical trials for use against traumatic brain injury, that attenuates mortalty in ECM mice when delivered intravenously or intra-peritoneally at 5g/kg. It was also determined that attenuation of mortality was via a perturbation of expression profiles of a network of pro-inflammatory and anti- inflammatory factors expressed during ECM pathogenesis. We determined that NRG-1 negatively regulates STAT3 and CXCL10 (a key biological determinant of fatal ECM) whereas it positively regulates HO-1. Therefore, we propose to assess the relevance of the networks perturbed by NRG-1 to ECM pathogenesis in our murine model and subsequently translate results to human subjects in the future. We hypothesize that NRG-1 attenuates CM mortality by down regulating CXCL10 and STAT3 activation and up regulating HO-1. The proposed study is designed to determine the mechanism by which NRG-1 regulates the heme-CXCL10- STAT3 system, and how it functions in protecting against fatal ECM. Three specific aims are proposed to test this hypothesis. In Specific Aim 1, we will characterize the cytoprotective efficacy of NRG-1 in ECM. In Specific Aim 2, we will determine the role of NRG-1 on heme-STAT3-CXCL10-HO-1 pathways in ECM. In Specific Aim 3, we will assess the role of NRG-1 in restoring integrity of heme damaged BBB in vitro. Understanding this mechanism will provide opportunities for discovery of new drug targets and interventions. NRG and other NRG-like agents present new opportunities to develop strategies that protect against fatal CM.